Capsule

Patent Version Content

Several FDA-approved drug labels may be available for clindamycin. AIDSinfo provides the following drug label solely as an example of the labels available for clindamycin. Inclusion or absence of a drug label on the AIDSinfo site does not imply endorsement or lack thereof by AIDSinfo. Search Drugs@FDA to access more information on clindamycin, including additional drug labels and any generic equivalents.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of CLEOCIN HCl and other antibacterial drugs, CLEOCIN HCl should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

WARNING

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including CLEOCIN HCl and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. difficle.

Because CLEOCIN HCl therapy has been associated with severe colitis which may end fatally, it should be reserved for serious infections where less toxic antimicrobial agents are inappropriate, as described in the INDICATIONS AND USAGE section. It should not be used in patients with nonbacterial infections such as most upper respiratory tract infections.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

DESCRIPTION

Clindamycin hydrochloride is the hydrated hydrochloride salt of clindamycin. Clindamycin is a semisynthetic antibiotic produced by a 7(S)-chloro-substitution of the 7(R)-hydroxyl group of the parent compound lincomycin.

The chemical name for clindamycin hydrochloride is Methyl 7-chloro-6,7,8-trideoxy-6-(1-methyl-trans-4-propyl-L-2-pyrrolidinecarboxamido)-1-thio-L-threo-α-D-galacto-octopyranoside monohydrochloride.

CLINICAL PHARMACOLOGY

Human Pharmacology

Absorption

Serum level studies with a 150 mg oral dose of clindamycin hydrochloride in 24 normal adult volunteers showed that clindamycin was rapidly absorbed after oral administration. An average peak serum level of 2.50 mcg/mL was reached in 45 minutes; serum levels averaged 1.51 mcg/mL at 3 hours and 0.70 mcg/mL at 6 hours. Absorption of an oral dose is virtually complete (90%), and the concomitant administration of food does not appreciably modify the serum concentrations; serum levels have been uniform and predictable from person to person and dose to dose. Serum level studies following multiple doses of CLEOCIN HCl for up to 14 days show no evidence of accumulation or altered metabolism of drug. Doses of up to 2 grams of clindamycin per day for 14 days have been well tolerated by healthy volunteers, except that the incidence of gastrointestinal side effects is greater with the higher doses.

Distribution

Concentrations of clindamycin in the serum increased linearly with increased dose. Serum levels exceed the MIC (minimum inhibitory concentration) for most indicated organisms for at least six hours following administration of the usually recommended doses. Clindamycin is widely distributed in body fluids and tissues (including bones). No significant levels of clindamycin are attained in the cerebrospinal fluid, even in the presence of inflamed meninges.

Excretion

The average biological half-life is 2.4 hours. Approximately 10% of the bioactivity is excreted in the urine and 3.6% in the feces; the remainder is excreted as bioinactive metabolites.

Special Populations

Renal Impairment

Serum half-life of clindamycin is increased slightly in patients with markedly reduced renal function. Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum.

Use in Elderly

Pharmacokinetic studies in elderly volunteers (61–79 years) and younger adults (18–39 years) indicate that age alone does not alter clindamycin pharmacokinetics (clearance, elimination half-life, volume of distribution, and area under the serum concentration-time curve) after IV administration of clindamycin phosphate. After oral administration of clindamycin hydrochloride, elimination half-life is increased to approximately 4.0 hours (range 3.4–5.1 h) in the elderly compared to 3.2 hours (range 2.1 – 4.2 h) in younger adults. The extent of absorption, however, is not different between age groups and no dosage alteration is necessary for the elderly with normal hepatic function and normal (age-adjusted) renal function1.

Microbiology

Clindamycin inhibits bacterial protein synthesis by binding to the 50S subunit of the ribosome. It has activity against Gram-positive aerobes and anaerobes as well as -some Gram-negative anaerobes. Clindamycin is bacteriostatic. Cross-resistance between clindamycin and lincomycin is complete. Antagonism in vitro has been demonstrated between clindamycin and erythromycin. Clindamycin inducible resistance has been identified in macrolide-resistant staphylococci and beta-hemolytic streptococci. Macrolide-resistant isolates of these organisms should be screened for clindamycin inducible resistance using the D-zone test.

Clindamycin has been shown to be active against most of the isolates of the following microorganisms, both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE section.

Gram-positive aerobes

Staphylococcus aureus (methicillin-susceptible strains)

Streptococcus pneumoniae (penicillin-susceptible strains)

Streptococcus pyogenes

Anaerobes

Prevotella melaninogenica

Fusobacterium necrophorum

Fusobacterium nucleatum

Peptostreptococcus anaerobius

Clostridium perfringens

At least 90% of the microorganisms listed below exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the clindamycin susceptible MIC breakpoint for organisms of a similar type to those shown in Table 1. However, the efficacy of clindamycin in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

Gram-positive aerobes

Staphylococcus epidermidis (methicillin-susceptible strains)

Streptococcus agalactiae

Streptococcus anginosus

Streptococcus oralis

Streptococcus mitis

Anaerobes

Prevotella intermedia

Prevotella bivia

Propionibacterium acnes

Micromonas ("Peptostreptococcus") micros

Finegoldia ("Peptostreptococcus") magna

Actinomyces israelii

Clostridium clostridioforme

Eubacterium lentum

Susceptibility Testing Methods

When available, the clinical microbiology laboratory should provide cumulative in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure based on dilution methods (broth, agar, or microdilution)2,3 or equivalent using standardized inoculum and concentrations of clindamycin. The MIC values should be interpreted according to the criteria provided in Table 1.

Diffusion Techniques

Quantitative methods that require the measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The standardized procedure2,4 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 2 mcg of clindamycin to test the susceptibility of microorganisms to clindamycin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 2 mcg clindamycin disk should be interpreted according to the criteria in Table 1.

Table 1. Susceptibility Interpretive Criteria for Clindamycin

Pathogen

Susceptibility Interpretive Criteria

Minimal Inhibitory Concentrations (MIC in mcg/mL)

Disk Diffusion (Zone Diameters in mm)

NA=not applicable

S

I

R

S

I

R

Staphylococcus spp.

≤ 0.5

1–2

≥4

≥21

15–20

≤14

Streptococcuspneumoniaeand otherStreptococcus spp.

≤0.25

0.5

≥1

≥19

16–18

≤15

Anaerobic Bacteria

≤2

4

≥8

NA

NA

NA

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small, uncontrolled technical factors from causing major discrepancies in interpretation.

A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test.2,3,4,5 Standard clindamycin powder should provide the MIC ranges in Table 2. For the disk diffusion technique using the 2 mcg clindamycin disk the criteria provided in Table 2 should be achieved.

Table 2. Acceptable Quality Control Ranges for Clindamycin to be Used in Validation of Susceptibility Test Results

QC Strain

Acceptable Quality Control Ranges

Minimum Inhibitory Concentration Range(mcg/mL)

Disk Diffusion Range(Zone Diameters in mm)

NA=Not applicable

ATCC® is a registered trademark of the American Type Culture Collection

When TestingAerobic Pathogens

Staphylococcus aureusATCC 29213

0.06–0.25

NA

Staphylococcus aureusATCC 25923

NA

24–30

StreptococcuspneumoniaeATCC 49619

0.03–0.12

19–25

When TestingAnaerobes

Bacteroides fragilisATCC 25285

0.5–2

NA

BacteroidesthetaiotaomicronATCC 29741

2–8

NA

Eubacterium lentumATCC 43055

0.06–0.25

NA

INDICATIONS AND USAGE

Clindamycin is indicated in the treatment of serious infections caused by susceptible anaerobic bacteria.

Clindamycin is also indicated in the treatment of serious infections due to susceptible strains of streptococci, pneumococci, and staphylococci. Its use should be reserved for penicillin-allergic patients or other patients for whom, in the judgment of the physician, a penicillin is inappropriate. Because of the risk of colitis, as described in the WARNING box, before selecting clindamycin, the physician should consider the nature of the infection and the suitability of less toxic alternatives (e.g., erythromycin).

Bacteriologic studies should be performed to determine the causative organisms and their susceptibility to clindamycin.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of CLEOCIN HCl and other antibacterial drugs, CLEOCIN HCl should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

CONTRAINDICATIONS

CLEOCIN HCl is contraindicated in individuals with a history of hypersensitivity to preparations containing clindamycin or lincomycin.

WARNINGS

Clostridium difficile associated diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including CLEOCIN HCl, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Severe Skin Reactions

Severe skin reactions such as Toxic Epidermal Necrolysis, some with fatal outcome, have been reported. In case of such an event, treatment should be permanently discontinued.

A careful inquiry should be made concerning previous sensitivities to drugs and other allergens.

Usage in Meningitis

Since clindamycin does not diffuse adequately into the cerebrospinal fluid, the drug should not be used in the treatment of meningitis.

PRECAUTIONS

General

Review of experience to date suggests that a subgroup of older patients with associated severe illness may tolerate diarrhea less well. When clindamycin is indicated in these patients, they should be carefully monitored for change in bowel frequency.

CLEOCIN HCl should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

CLEOCIN HCl should be prescribed with caution in atopic individuals.

Indicated surgical procedures should be performed in conjunction with antibiotic therapy.

The use of CLEOCIN HCl occasionally results in overgrowth of nonsusceptible organisms—particularly yeasts. Should superinfections occur, appropriate measures should be taken as indicated by the clinical situation.

Clindamycin dosage modification may not be necessary in patients with renal disease. In patients with moderate to severe liver disease, prolongation of clindamycin half-life has been found. However, it was postulated from studies that when given every eight hours, accumulation should rarely occur. Therefore, dosage modification in patients with liver disease may not be necessary. However, periodic liver enzyme determinations should be made when treating patients with severe liver disease.

The 75 mg and 150 mg capsules contain FD&C yellow no. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C yellow no. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

Prescribing CLEOCIN HCl in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Information for Patients

Patients should be counseled that antibacterial drugs, including CLEOCIN HCl, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When CLEOCIN HCl is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by CLEOCIN HCl or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Laboratory Tests

During prolonged therapy, periodic liver and kidney function tests and blood counts should be performed.

Drug Interactions

Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, it should be used with caution in patients receiving such agents.

Antagonism has been demonstrated between clindamycin and erythromycin in vitro. Because of possible clinical significance, these two drugs should not be administered concurrently.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed with clindamycin to evaluate carcinogenic potential. Genotoxicity tests performed included a rat micronucleus test and an Ames Salmonella reversion test. Both tests were negative.

Fertility studies in rats treated orally with up to 300 mg/kg/day (approximately 1.6 times the highest recommended adult human dose based on mg/m2) revealed no effects on fertility or mating ability.

Pregnancy

Teratogenic effects

Pregnancy Category B

In clinical trials with pregnant women, the systemic administration of clindamycin during the second and third trimesters, has not been associated with an increased frequency of congenital abnormalities.

Clindamycin should be used during the first trimester of pregnancy only if clearly needed. There are no adequate and well-controlled studies in pregnant women during the first trimester of pregnancy. Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed.

Reproduction studies performed in rats and mice using oral doses of clindamycin up to 600 mg/kg/day (3.2 and 1.6 times the highest recommended adult human dose based on mg/m2, respectively) or subcutaneous doses of clindamycin up to 250 mg/kg/day (1.3 and 0.7 times the highest recommended adult human dose based on mg/m2, respectively) revealed no evidence of teratogenicity.

Nursing Mothers

Clindamycin has been reported to appear in breast milk in the range of 0.7 to 3.8 mcg/mL. Because of the potential for serious adverse reactions in nursing infants, clindamycin should not be taken by nursing mothers.

Pediatric Use

When CLEOCIN HCl is administered to the pediatric population (birth to 16 years), appropriate monitoring of organ system functions is desirable.

Geriatric Use

Clinical studies of clindamycin did not include sufficient numbers of patients age 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experience indicates that antibiotic-associated colitis and diarrhea (due to Clostridium difficile) seen in association with most antibiotics occur more frequently in the elderly (>60 years) and may be more severe. These patients should be carefully monitored for the development of diarrhea.

Pharmacokinetic studies with clindamycin have shown no clinically important differences between young and elderly subjects with normal hepatic function and normal (age-adjusted) renal function after oral or intravenous administration.

ADVERSE REACTIONS

The following reactions have been reported with the use of clindamycin.

Hypersensitivity Reactions: Generalized mild to moderate morbilliform-like (maculopapular) skin rashes are the most frequently reported adverse reactions. Vesiculobullous rashes, as well as urticaria, have been observed during drug therapy. Severe skin reactions such as Toxic Epidermal Necrolysis, some with fatal outcome, have been reported (See WARNINGS). Cases of Acute Generalized Exanthematous Pustulosis (AGEP), erythema multiforme, some resembling Stevens-Johnson syndrome, and anaphylactoid reactions have also been reported.

Liver: Jaundice and abnormalities in liver function tests have been observed during clindamycin therapy.

Renal: Although no direct relationship of clindamycin to renal damage has been established, renal dysfunction as evidenced by azotemia, oliguria, and/or proteinuria has been observed.

Hematopoietic: Transient neutropenia (leukopenia) and eosinophilia have been reported. Reports of agranulocytosis and thrombocytopenia have been made. No direct etiologic relationship to concurrent clindamycin therapy could be made in any of the foregoing.

OVERDOSAGE

Significant mortality was observed in mice at an intravenous dose of 855 mg/kg and in rats at an oral or subcutaneous dose of approximately 2618 mg/kg. In the mice, convulsions and depression were observed.

Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum.

DOSAGE AND ADMINISTRATION

If significant diarrhea occurs during therapy, this antibiotic should be discontinued (see WARNING box).

To avoid the possibility of esophageal irritation, CLEOCIN HCl Capsules should be taken with a full glass of water.

Serious infections due to anaerobic bacteria are usually treated with CLEOCIN PHOSPHATE® Sterile Solution. However, in clinically appropriate circumstances, the physician may elect to initiate treatment or continue treatment with CLEOCIN HCl Capsules.

In cases of β-hemolytic streptococcal infections, treatment should continue for at least 10 days.

HOW SUPPLIED

CLEOCIN HCl Capsules are available in the following strengths, colors and sizes: